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Journal ArticleDOI

Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4.

TL;DR: This work presents a novel and scalable approach to gene expression engineering that allows for real-time annotation of gene expression changes in response to cancerigenicity and shows promise in finding novel and efficient treatments for cancer.
Abstract: 1 Laboratory For Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology (VIB), University of Ghent, Technologiepark, 927, Ghent B9052, Belgium 2 Salk Institute for Biological Studies, Gene Expression Laboratory, La Jolla, CA 92037, USA 3 Gene Expression and Diseases Unit, Institut Pasteur, Paris, France 4 The University of Texas Graduate School of Biomedical Sciences and department of Molecular Genetics, Section of Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA * Corresponding author: J-C Marine, Laboratory For Molecular Cancer Biology, VIB, Technologiepark, 927, Ghent B-9052, Belgium. Tel: þ 32-93-313-640; Fax: þ 32-93-313-516; E-mail: chris.marine@dmbr.ugent.be

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Citations
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Journal ArticleDOI
TL;DR: MDM2 physically interacts with S6a by anti bait coimmunoprecipitation by acting as a ‘spatially aggregating force’ to spruce up the phytochemical response of S6A by reprograming its immune defences.

8 citations

Journal ArticleDOI
TL;DR: It is suggested that the abundant expression of MDM4 in FLS may contribute to the hyperplasia phenotype of RA synovial tissues.

8 citations

Journal ArticleDOI
11 Dec 2017-PLOS ONE
TL;DR: Analysis of linear and stapled peptides comprising 6-Me-tryptophan provides mechanistic insight into dual Mdm2/Mdm4 antagonism and confirms L98 of Mdm4 as a mutable steric gate, and highlights a possible role of the flexible hinge region in determining Mdm 2/MDM4 plasticity.
Abstract: As primary p53 antagonists, Mdm2 and the closely related Mdm4 are relevant cancer therapeutic targets. We have previously described a series of cell-permeable stapled peptides that bind to Mdm2 with high affinity, resulting in activation of the p53 tumour suppressor. Within this series, highest affinity was obtained by modification of an obligate tryptophan residue to the non-natural L-6-chlorotryptophan. To understand the structural basis for improved affinity we have solved the crystal structure of this stapled peptide (M011) bound to Mdm2 (residues 6-125) at 1.66 A resolution. Surprisingly, near identity to the structure of a related peptide (M06) without the 6-chloro modification is observed. Further analysis of linear and stapled peptides comprising 6-Me-tryptophan provides mechanistic insight into dual Mdm2/Mdm4 antagonism and confirms L98 of Mdm4 as a mutable steric gate. The results also highlight a possible role of the flexible hinge region in determining Mdm2/Mdm4 plasticity.

8 citations

Journal ArticleDOI
01 Oct 2016
TL;DR: The results offer a rationale for the increased metastatic potential of p53 mutant human cancers with aberrant MdmX function and provide a caveat for the application of anti-MdmX treatment of tumors with compromised p53 activity.
Abstract: The MDMX (MDM4) oncogene is amplified or overexpressed in a significant percentage of human tumors. MDMX is thought to function as an oncoprotein by binding p53 tumor suppressor protein to inhibit p53-mediated transcription, and by complexing with MDM2 oncoprotein to promote MDM2-mediated degradation of p53. However, down-regulation or loss of functional MDMX has also been observed in a variety of human tumors that are mutated for p53, often correlating with more aggressive cancers and a worse patient prognosis. We have previously reported that endogenous levels of MdmX can suppress proliferation and promote pseudo-bipolar mitosis in primary and tumor cells derived from p53-deficient mice, and that MdmX-p53 double deficient mice succumb to spontaneously formed tumors more rapidly than p53-deficient mice. These results suggest that the MdmX oncoprotein may act as a tumor-suppressor in cancers with compromised p53 function. By using orthotopic transplantation and lung colonization assays in mice we now establish a p53-independent anti-oncogenic role for MdmX in tumor progression. We also demonstrate that the roles of MdmX in genome stability and in proliferation are two distinct functions encoded by the separate MdmX protein domains. The central Zn-finger domain suppresses multipolar mitosis and chromosome loss, whereas the carboxy-terminal RING domain suppresses proliferation of p53-deficient cells. Furthermore, we determine that it is the maintenance of genome stability that underlies MdmX role in suppression of tumorigenesis in hyperploid p53 mutant tumors. Our results offer a rationale for the increased metastatic potential of p53 mutant human cancers with aberrant MdmX function and provide a caveat for the application of anti-MdmX treatment of tumors with compromised p53 activity.

8 citations

Journal ArticleDOI
TL;DR: Two approaches that are under evaluating for targeting melanoma are focused on: defending against genome instability by p53 network restoration and disrupting cancer proteome by chaperone inhibition.
Abstract: Melanoma is the deadliest form of skin cancer worldwide. The rising melanoma incidence and mortality, along with its high propensity for metastasis highlights the urgency to identify more effective therapeutic targets. Approximately, one half of advanced melanoma bears a mutation in the BRAF gene that makes BRAF as an important therapeutic target. Significant clinical benefit is associated with BRAF and MEK inhibitors (MAPKi) on targeting patients with BRAF V600 mutations. However, the frequent and rapid development of acquired resistance still is the major challenge facing the melanoma. Several mechanisms by which melanoma passes the inhibitory effects of MAPKi have been characterized and clinically translated, but additional alternations of genetic and epigenetic regulators outside of MAPK and/or AKT networks occurs in a quarter of patients with acquired MAPKi resistance. These studies implicate that targeting signaling networks external MAPK or AKT pathways is critical. In this review, we will focus on two approaches that are under evaluating for targeting melanoma: (1) against genome instability by p53 network restoration and (2) disrupt cancer proteome by chaperone inhibition.

8 citations

References
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Journal ArticleDOI
19 Nov 1993-Cell
TL;DR: A gene is identified, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line and that could be an important mediator of p53-dependent tumor growth suppression.

8,339 citations

Journal ArticleDOI
06 Feb 2004-Science
TL;DR: In this article, the authors identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts.
Abstract: MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice.

4,397 citations

Journal ArticleDOI
15 May 1997-Nature
TL;DR: It is proposed that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.
Abstract: The p53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress. The activity of p53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins. The Mdm2 oncoprotein is a potent inhibitor of p53. Mdm2 binds the transcriptional activation domain of p53 and blocks its ability to regulate target genes and to exert antiproliferative effects. On the other hand, p53 activates the expression of the mdm2 gene in an autoregulatory feedback loop. The interval between p53 activation and consequent Mdm2 accumulation defines a time window during which p53 exerts its effects. We now report that Mdm2 also promotes the rapid degradation of p53 under conditions in which p53 is otherwise stabilized. This effect of Mdm2 requires binding of p53; moreover, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant p53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss. We propose that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.

4,311 citations

Journal ArticleDOI
15 May 1997-Nature
TL;DR: It is shown that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation, which may contribute to the maintenance of low p53 concentrations in normal cells.
Abstract: The tumour-suppressor p53 is a short-lived protein that is maintained at low, often undetectable, levels in normal cells. Stabilization of the protein in response to an activating signal, such as DNA damage, results in a rapid rise in p53 levels and subsequent inhibition of cell growth. Tight regulation of p53 function is critical for normal cell growth and development, and one mechanism by which p53 function is controlled is through interaction with the Mdm2 protein. Mdm2 inhibits p53 cell-cycle arrest and apoptic functions and we show here that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation. Endogenous levels of Mdm2 are sufficient to regulate p53 stability, and overexpression of Mdm2 can reduce the amount of endogenous p53. Because mdm2 is transcriptionally activated by p53, this degradative pathway may contribute to the maintenance of low p53 concentrations in normal cells. Furthermore, mechanisms regulating the Mdm2-induced degradation of p53 may play a role in controlling the extent and duration of the p53 response.

3,298 citations

Journal ArticleDOI
TL;DR: The data suggest that the MDM2 protein, which is induced by p53, functions as a ubiquitin ligase, E3, in human papillomavirus‐uninfected cells which do not have E6 protein.

1,962 citations